Bipolar disorder and
schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine,
viral infection, and prenatal or childhood stress may also predispose to
schizophrenia or
bipolar disorder. In cells, related stressors (
starvation, viruses,
cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha
kinases, which arrest
protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation
initiation factor eIF2B.
Growth factors increase
protein synthesis via
eIF2B activation and counterbalance this system. The control of
protein synthesis by eIF2-alpha
kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by
N-methyl-D-aspartate (
NMDA) and
metabotropic glutamate receptors. Many genes reportedly associated with both
schizophrenia and
bipolar disorder code for
proteins within or associated with this network. These include
NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4)
glutamate receptors,
growth factors (
BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha
kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the
eIF2B complex, mutations in which are responsible for
vanishing white matter disease. The convergence of natural and genetic risk factors on this area in
bipolar disorder and
schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these
psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.